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The increase in hemoglobin

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Leonid Livshits

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 Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCES

Special Issue: Hemoglobin Concentration for Assessing Anemia
ORIGINAL ARTICLE

The increase in hemoglobin concentration with altitude

varies among human populations
Max Gassmann,1,2,a Heimo Mairbäurl,3,a Leonid Livshits,1 Svenja Seide,4
Matthes Hackbusch,4 Monika Malczyk,5 Simone Kraut,5 Norina N. Gassmann,1
Norbert Weissmann,5 and Martina U. Muckenthaler6,a
1
Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Center for Integrative Human Physiology (ZIHP), University of
Zurich, Zurich, Switzerland. 2 Universidad Peruana Cayetano Heredia (UPCH), Lima, Peru. 3 Translational Lung Research
Center Heidelberg (TLRC), the German Center for Lung Research (DZL), Heidelberg, Germany. 4 Institute of Medical Biometry
and Informatics (IMBI), University Hospital Heidelberg, Heidelberg, Germany. 5 Excellence Cluster Cardiopulmonary System,
Justus-Liebig-University Giessen, University of Giessen and Marburg Lung Center, the German Center for Lung Research
(DZL), Heidelberg, Germany. 6 Pediatric Hematology, Oncology and Immunology, University Hospital Heidelberg, Molecular
Medicine Partnership Unit, University of Heidelberg, Translational Lung Research Center Heidelberg (TLRC), the German
Center for Lung Research, Heidelberg, Germany

Address for correspondence: Heimo Mairbäurl, University of Heidelberg, Translational Lung Research Center Heidelberg
(TLRH), the German Center for Lung Research (DZL) Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
heimo.mairbaeurl@med.uni-heidelberg.de

Decreased oxygen availability at high altitude requires physiological adjustments allowing for adequate tissue oxy-
genation. One such mechanism is a slow increase in the hemoglobin concentration ([Hb]) resulting in elevated [Hb]
in high-altitude residents. Diagnosis of anemia at different altitudes requires reference values for [Hb]. Our aim was
to establish such values based on published data of residents living at different altitudes by applying meta-analysis
and multiple regressions. Results show that [Hb] is increased in all high-altitude residents. However, the magnitude
of increase varies among the regions analyzed and among ethnic groups within a region. The highest increase was
found in residents of the Andes (1 g/dL/1000 m), but this increment was smaller in all other regions of the world
(0.6 g/dL/1000 m). While sufficient data exist for adult males and females showing that sex differences in [Hb] per-
sist with altitude, data for infants, children, and pregnant women are incomplete preventing such analyses. Because
WHO reference values were originally based on [Hb] of South American people, we conclude that individual ref-
erence values have to be defined for ethnic groups to reliably diagnose anemia and erythrocytosis in high-altitude
residents. Future studies need to test their applicability for children of different ages and pregnant women.

Keywords: anemia; excessive erythrocytosis; ethnicity; newborns; infants; pregnancy

Introduction lary blood to improve tissue oxygen supply.2 Arte-

rial oxygen content is increased by a decrease in
The decreased barometric pressure at high alti-
plasma volume that occurs within days upon ascent
tude results in reduced oxygen partial pressure and
to high altitude.3 In addition, a slow increase in
oxygen saturation of hemoglobin (Hb) in arterial
total Hb occurs.4,5 Despite those adjustments, tissue
blood.1 Hypoxemia stimulates ventilation, increases
oxygen supply remains insufficient, as impressively
cardiac output, alters the distribution of blood
indicated by decreased birth weight in high-altitude
flow, and enhances oxygen extraction from capil-
residents6 and reduced maximal oxygen uptake in
adults.7
Hypoxia stimulates erythropoiesis by complex
a
These authors equally contributed to this manuscript. molecular mechanisms (for review, see Ref. 8).

doi: 10.1111/nyas.14136
204 Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences.
Gassmann et al.
Briefly, hypoxia and reduced iron availability inac-
tivate prolyl hydroxylases (PHDs, especially PHD2)
in renal peritubular fibroblasts causing stabilization
of the α-subunit of hypoxia-inducible factor-2 alpha
(HIF-2α). HIF-2α dimerizes with HIF-1β. The het-
erodimer binds to the hypoxia-responsive element
of the EPO gene to stimulate transcription and to
increase erythropoietin (Epo) synthesis. Epo pro-
motes red blood cell maturation and proliferation
in the bone marrow, a process that requires iron. Its
availability is assured by the hormone erythrofer-
rone and platelet-derived growth factor BB. These
factors suppress the expression of hepcidin in the
liver so that hepcidin cannot induce degradation
of the iron exporter ferroportin in duodenal ente-
rocytes and in macrophages allowing for increased
iron absorption and release from stores. Iron bound
to transferrin is delivered to the bone marrow and
used for heme synthesis.8,9
Stimulation of erythropoiesis elevates the con-
centration of Hb ([Hb]). This process requires
weeks to months to reach a steady state. Early
reports indicate that the increase in [Hb] in sojourn-
ers to altitude is small at altitudes up to 3000 m but
increases more at higher altitudes.4 A similar pat-
tern of changes in [Hb] has also been observed in
high-altitude residents.10
Comparison of [Hb] in high-altitude natives and
long-term residents reveals the variation in [Hb].
For example, Tibetan people living at high alti-
tude have a much lower [Hb] than Han Chi-
nese upon moving to the Tibetan highlands.11
Moreover, at similar altitude, the [Hb] of Tibetan
and Ethiopian highlanders is lower than that of
Andean highlanders.12,13 The difference in [Hb]
among high-altitude natives may have a genetic
basis. In Tibetan people, a gain-of-function muta-
tion in the EGLN1 gene encoding for PDH2 results
in reduced HIF-2α levels, less Epo synthesis, and
decreased [Hb].11,14 These facts make the definition
of “normal” [Hb] in high-altitude residents difficult.
Dependency of [Hb] on age and sex, pregnancy,
socioeconomic, and nutritional status (with spe-
cial focus on iron supplies) adds complexity. How-
ever, the knowledge of [Hb] change with altitude
is of great clinical significance because [Hb] is the
first line of evidence for diagnosis of anemia. The
World Health Organization (WHO) suggests fac-
tors for correcting [Hb] with regard to altitude.10
The WHO also provides correction factors for [Hb]
Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences.
Hemoglobin levels at high altitude
differences among children, nonpregnant and preg-
nant women, and men. In terms of ethnicity, only
the difference between Caucasian people and peo-
ple with African extraction from the United States
had been officially considered so far, where the lat-
ter have a [Hb] ∼1 g/dL lower than the former.10,15
Factors can be combined to adjust [Hb] for the
detection of abnormalities and program surveys.
Importantly, the currently used adjustment factors
for altitude are based on [Hb] from children liv-
ing at altitudes between 1200 and 3000 m by apply-
ing a curvilinear fit.16 [Hb] of children of this age
is lower than that of adults. Because of age-related
differences between boys and girls,15 it is unclear
whether these factors actually apply for adults as
well. Correction factors for altitudes above 3000 m
were obtained from the literature on adult high-
altitude natives.4 There is convincing evidence that
these correction factors for altitude do not apply for
ethnically different natives living at high altitude in
different regions of the world.
The present study aimed at analyzing [Hb] with
increasing altitude, with age, sex, pregnancy, and
ethnicity and/or country and region of residence as
variables. The results are expected to allow for test-
ing the validity of the correction factors suggested
by the WHO.10 We performed a literature search on
the physiology of life at high altitude and extracted
[Hb] for meta-analysis. Results show increases in
[Hb], but with a distinctly higher response in South
American people compared with all others. Sub-
grouping by age was impossible because of insuf-
ficient data. This points to the need for further
exploration of [Hb], at best worldwide, to fully char-
acterize its changes with altitude and the variability
of this change depending on ethnicity.
Methods
We aimed at analyzing the distribution of [Hb] con-
centration for infants, children, and adult males and
females, as well pregnant women with regard to
altitude in as many regions of the world as pos-
sible based on results published on the physiol-
ogy of adaptation to moderate and high altitude.
Unfortunately, the actual classification of data did
not permit such detailed analysis (see below and
Supplementary Information, online only). A litera-
ture search on high-altitude medicine and physiol-
ogy was performed in June 2017 in PubMed of the
205
Hemoglobin levels at high altitude
Table 1. Flowchart of data identification
1623 data sources extracted
1513 data sources excluded because:
375 not relevanta
304 sojourners <1 yearb
63 normobaric hypoxia
665 sexes combined or not reported
49 age not well definedc
26 mentioned smokers and nonsmokers
22 no measure of variationd
3 unconventional methods of measuring [Hb]
6 only 1 subject
110 Data sources includede
a Disease and treatment studies without control group, case
reports, measurements on animals and cells, mathematical mod-
els, reviews, or educational materials.
b Also includes studies on high-altitude training, intermittent
hypoxia, and measurements after return from a trekking/
climbing expedition.
c No age or age-range is provided; children and adults are com-
bined.
d No SD or 95% confidence interval; SEM without “n.”
e Many data sources contained several sets of data, for example,
different age groups, different ethnicities, and men and women
(see Table 2).
National Library of Medicine of the United States,
using “hemoglobin,” “hematocrit,” “oxygen trans-
port,” and “high altitude” or “highlanders” as key-
words. This resulted in 1553 hits. We surveyed an
additional 70 publications quoted in other work on
high-altitude physiology that had not appeared in
the above-mentioned search. Our search did not
include other summarized data and national sur-
veys. [Hb] was extracted from 110 publications.
Several studies contained data on more than one
group, such as men and women or different alti-
tudes. [Hb] has been measured spectrophotometri-
cally and by the use of various automated systems.
Exclusion criteria are listed in Table 1.
Inclusion and exclusion criteria of data
Only those data were included in our analy-
sis where authors stated explicitly to have stud-
ied healthy individuals, which is an inevitable
criterion to estimate “physiological” responses to
high altitude. This decision excluded publica-
tions, where [Hb] was very low and with a like-
lihood of anemia without further definition of
its cause. We also excluded publications explic-
itly mentioning that the study group included
206 Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences.
Gassmann et al.
smokers. However, there were insufficient num-
bers of publications to form a separate subgroup
on smokers. In 2005, Leon-Velarde et al. suggested
that a cutoff of 21 g/dL for men and 19 g/dL
for women defines high-altitude residents suffering
from chronic mountain sickness (CMS).17 Based on
this report, some studies published after 2005 stated
to have omitted individuals with [Hb] above those
thresholds. Thus, we cannot exclude that in studies
before the appearance of this publication subjects
possibly suffering from CMS had been included in
studies.
Grouping
We further aimed to form subgroups with narrow
age ranges of children and juveniles because the
[Hb] increases until the maturity is reached.15 How-
ever, this was impossible because the age of the sub-
jects recruited in published studies was inconsistent
and/or incomplete. In addition, data were excluded
if [Hb] values for adult males and females, pregnant
or nonpregnant, were not reported separately.
We further attempted to subgroup ethnicities,
regions, and/or countries of the world based on
reported differences in [Hb]. Reports describe
“Andean, Tibetan or Ethiopian patterns of adapt-
ation”18 and genetic mutations associated with [Hb]
in Tibetan people.11,14
For calculations, we assigned uncorrected [Hb]
values to the nearest altitude provided in the publi-
cation. Groups of 1000-m ranges starting at sea level
were formed. Several publications reported the alti-
tude where the study had been performed (in a hos-
pital or a city) without mentioning the exact altitude
of residence of the subjects. If ranges of altitudes of
residence were provided for a mean value of [Hb],
then the mean altitude was used in our analysis.
Mean [Hb] and the range of validity for the
defined subgroups (newborn, juveniles, adult men
and women, and pregnancy) with regard to ranges
of altitude for various regions of the world are pre-
sented in Table 2. Details on the grouping variables
used for the classification of altitude ranges, age
groups, and of ethnicity/region/country are listed
in Table S1 (online only). The countries included
in the analysis are summarized in Table S2 (online
only).
Statistical analysis
The meta-analysis was based on mean values of
[Hb] (not adjusted for altitude) and corresponding
Gassmann et al. Hemoglobin levels at high altitude

Table 2. Hemoglobin concentration at different altitudes above sea level, in relation to age, sex, and
region/country/ethnicity
Gender/age/ 0−999 m 1000−1999 m 2000−2999 m 3000−3999 m 4000−4999 m ≥5000 m
pregnancy N/ds/ N/ds/ N/ds/ N/ds/ N/ds/ 95%- N/ds/
status Mean 95%-CrI refs Mean 95%-CrI refs Mean 95%-CrI refs Mean 95%-CrI refs Mean 95%-CrI refs Mean CrI refs

The United States of America

Newborn 17.2 nc 44/
1/1
M-juvenile 12.8 11.0–14.5 2248/
8/5
F-juvenile 12.6 11.2–13.9 2113/
8/5
M-adult 14.7 13.3–16.0 7440/ 15.6 13.3–17.9 1296/ 16.1 14.1–19.0 34/ 16.4 14.7–18.2 63/ 17.5 nc 4/
18/15 7/16 4/17 5/18 1/17
F-adult 13.0 11.7–14.3 6900/ 13.4 0.0–26.8 129/ 16.0 nc 6/ 15.0 −0.4–30.8 50/
17/45 3/46 1/17 3/47
F-pregnant 12.6 9.5–15.7 10/
1/65
Central/South America-rest
Newborn 19.0 nc 53/
1/75
M-juvenile
F-juvenile 13.1 nc 138/ 15.7 nc 470/ 16.1 nc 96/ 17.6 nc 42/
1/11 2/12 2/13 1/13
M-adult 14.9 11.9–18.0 730/ 15.3 7.7–22.9 589/ 16.6 13.3–19.8 607/ 17.9 13.8–22.0 1803/ 19.5 16.2–22.8 2395/ 20.3 nc 80/
6/S19 2/20 8/21 13/22 17/23 2/24
F-adult 13.7 nc 142/ 14.1 nc 201/ 14.8 13.7–15.9 378/ 15.4 11.0–19.8 562/ 17.0 14.4–19.6 1459/ 18.2 nc 78/
2/48 2/49 7/50 8/51 9/52 2/24
F-pregnant 11.3 nc 8449/ 13.7 12.7–14.8 24833/ 14.1 nc 2305/
2/66 5/67 2/68
South America-Quechua
Newborn
M-juvenile 15.4 nc 30/
1/6
F-juvenile
M-adult 17.8 nc 106/ 16.4 14.5–18.2 122/
2/25 7/6
F-adult
F-pregnant
Africa-rest
Newborn
M-juvenile
F-juvenile
M-adult 14.3 12.4–16.2 475/ 15.4 14.0–16.9 623/ 16.1 nc 10/
5/26 6/27 1/28
F-adult 12.9 12.1–13.7 811/ 13.7 12.0–15.5 959/
6/53 6/54
F-pregnant 11.9 1.0–22.8 3736/ 12.7 nc 100/
3/69 1/69
Africa-Ethiopia
Newborn
M-juvenile
F-juvenile
M-adult 15.4 11.7–19.1 256/ 17.1 14.7–19.5 573/
8/29 9/30
F-adult 14.3 11.8–16.8 109/ 14.2 9.8–18.7 597/ 15.6 13.3–18.0 389/
6/55 4/56 8/57
F-pregnant
Asia-rest
Newborn 16.0 13.8–18.2 2664/ 17.0 nc 45/ 18.7 nc 574/
5/2 1/3 2/2
M-juvenile
F-juvenile
M-adult 14.7 12.1–17.3 369/ 16.2 9.2–23.3 1868/ 16.7 nc 114/ 16.0 nc 94/
4/31 4/32 1/33 1/33
F-adult 12.1 nc 288/ 13.3 10.3–16.3 1557/
1/58 4/59
F-pregnant 10.4 nc 80/ 12.3 nc 323/ 12.9 nc 20/
2/70 2/71 1/72

Continued

Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences. 207
Hemoglobin levels at high altitude Gassmann et al.

Table 2. Continued

Gender/age/ 0–999 m 1000–1999 m 2000–2999 m 3000–3999 m 4000–4999 m ≥5000 m

pregnancy N/ds/ N/ds/ N/ds/ N/ds/ N/ds/ 95%- N/ds/
status Mean 95%-CrI refs Mean 95%-CrI refs Mean 95%-CrI refs Mean 95%-CrI refs Mean 95%-CrI refs Mean CrI refs

Han Chinese people

Newborn 18.6 12.5–24.7 15/
1/4
M-juvenile 13.7 nc 144/ 14.5 12.1–16.8 515/ 15.2 11.7–18.8 54/ 17.1 nc 6/
1/7 12/8 5/9 1/7
F-juvenile 13.7 nc 108/ 14.1 11.5–16.6 350/ 15.4 nc 18/ 15.6 nc 5/
1/7 12/8 1/7 1/7
M-adult 15.5 14.0–17.1 2185/ 15.7 11.0–20.5 1320/ 17.5 14.5–20.5 926/ 18.9 16.6–21.2 1328/ 19.6 nc 30/
11/34 3/35 15/36 7/37 2/7
F-adult 13.4 12.7–14.0 2609/ 14.3 nc 335/ 15.0 12.9–17.0 639/ 16.5 nc 227/ 19.6 nc 30/
8/60 2/7 13/61 2/7 2/7
F-pregnant 14.0 nc 68/
2/73
Tibetan
Newborn 16.7 nc 15/
1/4
M-juvenile 13.4 nc 42/ 13.9 11.3–16.5 976/ 14.9 13.2–16.6 342/ 14.6 nc 12/
1/7 13/10 7/8 1/7
F-juvenile 13.4 nc 58/ 13.7 11.3–16.1 950/ 14.2 nc 227/ 14.5 nc 10/
1/7 13/10 2/14 1/7
M-adult 14.2 nc 14/ 14.8 10.7–19.0 635/ 16.3 14.4–18.2 1298/ 16.8 14.8–18.5 770/ 16.2 11.8– 74/
1/38 4/35 20/39 17/40 20.6 3/41
F-adult 12.9 nc 326/ 14.4 12.8–16.1 1339/ 15.4 12.7–18.2 809/ 15.2 9.1– 101/
2/7 25/62 14/63 21.2 3/41
F-pregnant 12.5 11.2–13.9 2243/
3/74
Sherpa
Newborn
M-juvenile
F-juvenile
M-adult 14.2 nc 14/ 16.9 15.6–18.3 198/ 17.0 nc 28/
1/42 4/43 1/44
F-adult 14.8 nc 211/ 15.3 nc 23/
2/64 1/44
F-pregnant

Note: Mean values (mean) of the Hb concentration (g/dL) and 95% credible intervals (95% CrI) were calculated from reported
mean values, number of individuals (n) in the number of datasets (ds), and standard deviations as reported in the respective set of
publications (“refs;” see below). Values for Hb are rounded to one decimal. Note that one reference may contain more than one dataset.
Numbers shown in italics and in gray-shaded fields indicate that only one or two datasets were available. In this case, the mean values
of the one or two studies are shown, and the 95% CrI field contains “nc” indicating that from these datasets no convergent range can
be calculated, and that the mean value is thus not reliable. In general, a wide 95% CrI indicates high uncertainty of the estimate of the
mean. Altitudes (or mean values when ranges were provided in the publication) were sorted into the respective categories. Values on
newborns were obtained immediately after delivery. The group “juveniles” covers the age range between 1 and 15 years, adults are
subjects older than 15 years of age. Abbreviations: F, female; M, male.
Refs: 1;6 2;37 3;50 4;38 5;15 6;42 7;41 8;40,41,51 9;40,41 10;40,41,51,52 11;53 12;53,54 13;55 14;41,51 15;15,56–59 16;56–60 17;57 18;48,57 19;4,33,61–64
20;33,61 21;33,61,65–69 22;4,12,33,70–74 23;4,33,55,63,64,75–79 24;55 25;27,80 26;81–83 27;82,84–86 28;87 29;88–91 30;13,88–91 31;92–94 32;92,95,96
33;93 34;28,97–101 35;41,97 36;40,41,98,99,101–105 37;40,41,97,106–108 38;28 39;40,41,74,98,99,102–105,109–112 40;11,40,41,97,106,111,113–115 41;41,116
42;117 43;27,118–121 44;115 45;15,56,57,122 46;56,57 47;6,57 48;61,66 49;61 50;61,65,67,69,123 51;12,43,74,124–128 52;55,75,76,125,126,129 53;81–83,130
54;82,84,85,130,131 55;89–91 56;132 57;89–91,133 58;92 59;92,95,96 60;98–100 61;40,41,98,99,102,105,134 62;40,41,74,98,99,102,105,109,110,112,134,135
63;11,40,41,109,113,114 64;118,121 65;6 66;68,136 67;136 68;136,137 69;138 70;139,140 71;139,141 72;140 73;134,142 74;135,142,143 75.39

standard errors. If publications reported medi-
ans and interquartile ranges, mean and standard
errors were calculated using a dedicated statistical
algorithm.19,20
Individual study results were combined within
prespecified subgroups that were defined with
regard to categories of ethnicity, altitude, sex, and
age (see Table S1, online only). Within those sub-
groups, a pooled mean effect along with a 95%
equal-tailed credible interval was derived by fit-
ting a Bayesian random-effects model to the data.
In a Bayesian meta-analysis, prior information is
combined with observed data to obtain a poste-
rior distribution of the effect of interest, as we are

208 Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences.
Gassmann et al. Hemoglobin levels at high altitude

23 A adult females 23 B adult males

22 USA 22
Central−/South American
African
21 Africa − Ethiopian 21
Asian
20 Han 20
Tibetan

19 19

18 18
Hb in g/dL

Hb in g/dL
17 17

16 16

15 15

14 14

13 13

12 12

11 11

0 1000 2000 3000 4000 5000 0 1000 2000 3000 4000 5000

Altitude in m Altitude in m

Figure 1. Meta-regression analysis of changes in the hemoglobin concentration with altitude of residence in adult females (A)
and males (B). Data are grouped by ethnicity or region/country. Each point indicates the mean value of a dataset reported in the
literature (see references to Table 2). The size of each dot reflects its precision and thus its influence on the regression. Lines are
shown where significant (full lines) or a trend (P < 0.1; dashed line) of differences to the reference group (the U.S. females; gray
line) existed in intercept or slope (see details in Table 3).

mainly interested in an initial summary of avail- as a reference population. Because of insufficient

able data and the underlying distribution of the
population’s [Hb].21 Given the data, the resulting
95% credible interval includes the true population
value of Hb with probability of 95%. Due to limited
preliminary information, flat (improper) uniform
priors on the mean effect and the between-study
heterogeneity were used.
Heterogeneity was explored by the I2 -statistic,
calculated with the highest posterior probability of
the between studies variance. A sensitivity analysis
was conducted by excluding all studies before 1980
(chosen arbitrarily) to account for possible hetero-
geneity in methods and design introduced by early
investigations.
To investigate the influence of the altitude on
[Hb], we performed a meta-regression based on
a random-effects model, with altitude (continuous
scale), sex (female/male), ethnicity/region/country
(the United States, Central/South America, Africa,
Africa-Ethiopia, Asia (Tibet excluded), Tibetan Han
Chinese, and Tibetan people), and the interaction of
altitude and ethnicity/region as covariates. We ran-
domly chose native women from the United States
data, only data of adults were taken into account
in the meta-regression approach. The South Amer-
ican Quechua and Himalayan Sherpa people are
excluded for the same reason.
The analyses were carried out by the software R
(R Core Team (2017)), a language and environment
for statistical computing (R Foundation for Statis-
tical Computing, Vienna, Austria; https://www.R-
project.org/). For the Bayesian analysis, we used the
R package bayesmeta, version 1.5.,22 and for meta-
regression the R package meta, version 4.7-2-2.23
Results
Table 2 summarizes [Hb] values of various sub-
groups at different altitudes. Figure 1 and Table 3
summarize the result of a multifactorial regression
analysis on [Hb] of adult females and males only.
One important observation is that data published
on the physiology of acclimatization to high altitude
in residents are incomplete. In Table 2, many entries
are lacking indicating that corresponding data were
not available. Fields shaded in gray containing a
mean value indicate that analysis did not reach

Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences. 209
Hemoglobin levels at high altitude Gassmann et al.

Table 3. Multiple meta-regression model describing the change in the [Hb] with increasing altitude for adult
females and males in dependence of ethnicity/region/country
Beta SE P value CI.lb CI.ub

(A) Intercept = sea level (Hb; g/dL)

Reference: U.S. females 12.703 0.137 0.000 12.435 12.970
Males +1.925 0.079 0.000 1.771 2080
Additional correction of intercept for:
South American people −0.331 0.235 0.159 −0.792 0.130
African (not Ethiopian) people −0.188 0.277 0.498 −0.731 0.356
Ethiopian people +0.020 0.345 0.953 −0.656 0.696
Asian (not Han or Tibetan) people +0.020 0.341 0.953 −0.649 0.688
Han Chinese people +0.432 0.210 0.039 0.021 0.843
Tibetan people −0.806 0.418 0.054 −1.625 0.013
(B) Slope = change with altitude (Hb; g/dL/1 km)
Reference group 0.617 0.098 0.000 0.425 0.809
Additional correction of slope for:
altitude∗South-American people 0.433 0.112 0.000 0.213 0.653
altitude∗African people 0.112 0.234 0.631 −0.347 0.571
altitude∗Ethiopian people 0.109 0.147 0.462 −0.180 0.397
altitude∗Asian people 0.020 0.238 0.935 −0.446 0.485
altitude∗Han-Chinese people 0.064 0.111 0.565 −0.154 0.282
altitude∗Tibetan people 0.063 0.142 0.659 −0.215 0.340

Note: As an example, the Hb for a male South American (non-Quechua) living at an altitude of 4500 m (4.5 km) can be estimated as:
Hb = 12.703 g/dL + 1.925 g/dL – 0.331 g/dL + 0.617 g/dL/km ∗ 4.5 km + 0.433 g/dL/km ∗ 4.5 km = 19.022 g/dL, where
12.703 g/dL is the reference Hb of an adult woman living in the United States, 1.925 g/dL is the difference between men and women,
–0.33 g/dL is the difference in the intercept between the U.S. and Andean population (independent of sex), 0.617 g/dL/km ∗ 4.5 km is
the increase in Hb with altitude for the reference-population, and 0.433 g/dL/km ∗ 4.5 km is the additional increase in Hb with altitude
in the Andean population. For comparison, the measured value is 19.5 g/dL (16.2–22.8) as shown in Table 2, suggesting adequacy of
the present equation.
Calculation and comparisons were made using Hb values from adult female residents (randomly chosen) from the United States
as reference (age >15 years, where the actual altitude provided in the respective publication was used for calculations). Quechuas
and Sherpas were not included because of the narrow range of altitudes, where data were available. The model does not include
age and pregnancy due to incomplete datasets. (A) Calculated intercept (i.e., sea-level value) and its correction for sex and ethnic-
ity/region/country. (B) Change in Hb with altitude for the reference population (independent of sex) and the additional correction
factors for individual ethnicity/region/country.
Beta, the respective value; SE, standard error; P value, level of statistical significance; CI.lb and CI.ub, lower and upper boundary of
the confidence interval, respectively.

congruence (range = nc) because either only one
publication was available or the published data were
highly variable with unreasonably wide 95% inter-
vals (95% CrI). Taken together, datasets covering
wide ranges of altitudes of residence could only be
obtained in nonpregnant adult females and males.
Table 2 serves as a look-up table to check whether a
measured [Hb] is within the normal range or not.
Because of incomplete datasets, multiple-
regression analysis could only be performed on
adult males and nonpregnant females. Also, data
from Quechua and Sherpa people were omitted
from multiple-regression analysis because they
originate from narrow ranges of altitudes. The anal-
ysis of the remaining groups shows that calculated
[Hb] at sea level (Table 3A) differs among residents
of different ethnicity or region or country. As ref-
erence [Hb] value, we arbitrarily chose the data
on healthy female U.S. residents. Based on these
data, we exemplify how to calculate the predicted
Hb value of a male South American highlander
living at 4500 m of altitude. In contrast to the South
American population, Tibetan males and females
tend to have a [Hb] at sea level that is 0.8 g/dL lower
than the reference (P = 0.0534). By contrast, the
calculated sea level [Hb] for Han Chinese people
was significantly higher (+0.4 g/dL; P = 0.0389)
than [Hb] of the reference group. The model also

210 Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences.
Gassmann et al.
shows that overall, as expected, [Hb] of males is
1.9 g/dL higher than that of females (P < 0.0001).
Our regression analysis confirms previous results
showing that [Hb] increases with altitude indepen-
dent of ethnicity or region or country of the resi-
dents (Table 3B). It further shows that independent
of sex, [Hb] of the reference group (North Amer-
ican women) increased by 0.62 g/dL per 1000 m
of altitude (P < 0.0001). Interestingly, a higher
rate of increase was found in South American resi-
dents compared with the U.S. reference group (1.05
g/dL/1000 m; P < 0.0001). By contrast, the increase
in [Hb] with altitude in all other groups was not dif-
ferent from the reference.
Discussion
Our meta-analysis demonstrates an increased [Hb]
in male and female high-altitude residents across
all age ranges independent of ethnicity and coun-
tries of residence. However, the high-altitude resi-
dents from the Andes are exceptional in that they
show a significantly more pronounced increase in
[Hb] compared with all other populations of the
world. This finding points to different adaptation
strategies related to oxygen transport among differ-
ent ethnicities. The observed heterogeneity implies
that one single set of correction factors for [Hb]
at altitude as suggested by the WHO for the diag-
nosis of anemia cannot be applied worldwide. Our
data analysis further revealed that research on high-
altitude acclimatization so far focused mainly on
adult women and men, whereas research on new-
borns, children of different age, pregnancy, but
also on pathophysiologic conditions, such as smok-
ing and cardiovascular and respiratory diseases, is
sparse. As a result of our literature survey, we gener-
ated look-up tables (Table 2) for judging whether a
measured [Hb] is within the normal range. In these
tables, we also indicated where information is lack-
ing and where future studies are required to fill these
gaps.
[Hb] at high altitude differs among
ethnicities/countries
A slow increase in erythrocyte count during a
sojourn at high altitude of mostly Caucasian low-
landers has been first described by Viault24 over a
century ago. It was later noticed that also native
highlanders of the Andes have elevated [Hb] (sum-
marized by Ref. 4). However, heterogeneity has
Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences.
Hemoglobin levels at high altitude
been reported among Andean highlanders indi-
cating that when living, for example, at 3600 m,
Quechua people had a lower [Hb] (15.8 g/dL) than
Aymara (18.2 g/dL). Interestingly, there was no dif-
ference between these populations at sea level.4,25
Later, it has been reported that also [Hb] of natives
of the Tibetan plateau,11,26 Himalayan sherpas,27
and residents of the Ethiopian highlands was lower
than most of the Andean population.13 Our meta-
analysis is in line with these results (Table 2)
and indicates significantly higher [Hb] in non-
Quechua Andean adult women and men living at
altitudes >3000 m than residents of similar altitude
ranges from most other countries/regions around
the world.
This difference points toward varying set-points
for adjusting [Hb] in different ethnicities residing at
moderate to high altitudes. Interestingly, such dif-
ferences have also been detected at sea level, where
people of South and West African ancestry have
a lower [Hb] than Caucasian people. This differ-
ence is evident at all ages, in children and adult
of both sexes.15 Such differences are not apparent
in other ethnicities, with the exception of Tibetan
people, who show lower [Hb] than Han Chinese
people at low altitude.28 Our results obtained from
multiple regression analysis (Table 3) support this
notion.
The molecular basis for the lower [Hb] in Tibetan
people is at least in part explained by polymor-
phisms in genes affecting the oxygen sensing pro-
cess, the expression of hypoxia-related genes, and
Hb synthesis. High-frequency missense mutations
were described in the EGLN1 gene encoding PHD2,
the oxygen sensor. These genetic variants exhibit a
lower K(m) value for oxygen, suggesting increased
HIF degradation under hypoxic conditions. This
mutation originated approximately 8000 years ago
and seems to protect Tibetan people from excessive
erythrocytosis at high altitude.29 In addition,
genome-wide analyses revealed a positive selection
of haplotypes in the EPAS1, EGLN1, and PPAR1
genes encoding HIF-2α, HIF-prolyl-hydroxylase
2, and peroxisome proliferator−activated recep-
tor α, respectively, which were associated with
decreased [Hb] in Tibetan people.11,30 Of note, we
have observed that this oxygen sensing mechanism
precisely senses altitude differences of 300 m even in
low to moderate altitudes (M.G., data unpublished,
in preparation).
211
Hemoglobin levels at high altitude
Taken together, the pronounced differences in
[Hb] among high-altitude residents from different
countries around the world point toward alterations
in the response to hypoxia among ethnicities. This
differential response also reflects on the need for
establishing normal [Hb] values in high-altitude
residents according to their ethnicity to be able to
correctly diagnose anemia and erythrocytosis.
Degree of increase in [Hb] with altitude
Our multiple regression analysis revealed
that the magnitude of increase in [Hb] var-
ied considerably among ethnicities/countries
(Fig. 1). A greater increase in [Hb] with alti-
tude was detected in most South American
natives (Hb = 1.05 g/dL/1000 m) compared
with all others (Hb = 0.62 g/dL/1000 m;
see Table 3). Unfortunately, we were unable to
calculate such slopes for Quechua and Sherpa
people because they inhabit only narrow ranges of
altitudes. Figure 1 also shows that in those regions
with the lower Hb the regression lines approxi-
mately run parallel and slopes were not significantly
different (Table 3B). However, the offsets, which
represent a calculated [Hb] at sea level, were differ-
ent (Table 3A). This finding indicates that oxygen
sensitivity of the erythropoietic system is compara-
ble in the populations with similar Hb, whereas
an increased oxygen sensitivity of the erythropoi-
etic system may account for the greater Hb in
the Andean population. Additional explanations
may include differences in the hypoxic ventila-
tory response of the Andean residents, who show
elevated end-tidal CO2 compared with Tibetan
high-altitude residents and corresponding lower
arterial SO2 .31 The decreased oxygen sensitivity
of respiratory control results in decreased arterial
oxygen content, which then drives erythropoiesis.
We chose to analyze the data with a linear
model because grouped data do not allow for more
complex curve fitting. The increase in [Hb] with
altitude has also been modeled using nonlinear
functions, which appears appropriate based on
the sigmoidal shape of the oxygen dissociation
curve resulting in a disproportionate decrease in
arterial oxygen saturation at altitudes over 2000
meters. However, nonlinear functions only appear
appropriate when arterial oxygen saturation and
thus oxygen content is the only factor affecting
[Hb]. A polynomial fit of higher orders published
212 Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences.
Gassmann et al.
by the Center for Disease Control is used for adjust-
ing [Hb] in program surveys; it is based on data
covering altitudes ranging from sea level to 3000
meters.16 Winslow and Monge32 applied another
polynomial fit for data analysis of Chilean workers,
where the highest study point was at 4600 meters.33
Yet, another approach used the shape of the oxygen
dissociation curve and was based on data obtained
in Ecuadorian children living up to 3400 meters.34
In 1945, Hurtado et al.4 estimated correction values
from the published literature obtained at locations
up to 5350 meters. The linear approach applied in
the present study appears to give a very good fit for
women of all different ethnicities/regions (Fig. 1A).
Interestingly, a deviation from linearity appears to
exist in South American men. It is possible that this
disproportionate Hb is contributed by samples
obtained from miners,4,33,35 who intermittently
work at altitudes higher than their altitude of resi-
dence and who are often exposed to dust and badly
ventilated mining tunnels. Both of these condi-
tions increase the severity of hypoxia resulting in
more pronounced erythropoiesis. Another reason
for elevated [Hb] is CMS that is associated with
polycythemia.32 Unfortunately, most publications
do not state clearly whether individuals suffering
from CMS had been omitted. It was only in 2005
that a cutoff [Hb] of 21 g/dL in men and 19 g/dL in
women has been defined above which an individu-
als’ [Hb] might indicate CMS.17 Therefore, beyond
2005, most studies state that individuals with a [Hb]
above this threshold had been omitted, assuming
that they suffered from CMS but often without
clinical verification of this diagnosis. This may not
have been the case in studies before 2005, which
would result in elevated mean [Hb] in those studies.
Children. Our analysis fails to provide reference
ranges for the diagnosis of anemia in both chil-
dren and pregnant women because data are scarce
in the literature (Table 2). These groups are partic-
ularly prone to an increased risk when anemic. At
birth, [Hb] is high. It then decreases during the next
few months and then increases again to reach sta-
ble values in females at the age of approximately 13–
15 years and in males between 17 and 20 years. At
this age, the [Hb] of males is approximately 2 g/dL
higher compared with females.15,36 [Hb] of chil-
dren of African origin living in the United States is
approximately 1 g/dL lower than that of Caucasian
Gassmann et al.
people.15 It is currently not well understood
whether the magnitude of change in [Hb] related
to altitude is the same in children and adults in dif-
ferent regions of the world. In Saudi Arabia, [Hb]
tended to be elevated in newborns at 2700 m rela-
tive to those born at low altitude.37 Niermeyer and
colleagues found that [Hb] in Tibetan newborns
was lower compared with Han Chinese newborns.38
There was no difference in [Hb] in Puno (3840 m)
between newborn indigenous Aymaras, Hispanic,
and mixed origin people.39 [Hb] increased linearly
in Quechua boys by approximately 2.7 g/dL between
the age of 6 and 21 years, which is in the same
range as found in Caucasian boys15 and similar to
the age-related increase of Tibetan and Han Chi-
nese children.40,41 [Hb] of children living in the
Andes has been shown to be approximately 0.5–1.0
g/dL higher than Han Chinese children at compa-
rable altitude.42 Together, these results indicate dif-
ferences in children’s [Hb] between ethnical groups
that appear to be similar to those observed in adults
(Table 2 and Fig. 1). Furthermore, the age-related
increase in [Hb] persists in children native to high
altitude.
Pregnancy. Plasma volume expansion during
pregnancy reduces [Hb], and this “dilution” might
be interpreted as anemia. Thus, correction factors
have been suggested,16 but these factors apply to
low altitude only. However, there are some indica-
tions that changes are similar in European people
and Andean natives living in La Paz, Bolivia, at
3600 meters.43,44
Diagnosing anemia. Because of the increase in
[Hb] with altitude and the differences in this
increase among regions/ethnicities, it is a challenge
to determine whether a measured [Hb] of a high-
altitude resident shall be considered as clinically
“normal” or not. The mean values and ranges of
[Hb] listed in Table 2 will support this diagnosis.
Measured [Hb] outside the indicated ranges has
to be considered abnormally low or high for the
respective altitude. However, the utility of Table 2
is limited by the quality and availability of data in
the literature. A large number of imprecise (gray-
shaded) or even missing values, in particular for
newborns, children, and pregnant women, are indi-
cated in Table 2.
Another possibility to detect anemia in high-
altitude residents is the application of cutoff values
Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences.
Hemoglobin levels at high altitude
for age, sex, and pregnancy suggested by the WHO
for low altitude10 and the use of correction values
for the altitude of residence. Care must be taken
into account for the differences observed between
regions (ethnicity), as we report here. Based on
our analyses, we strongly recommend using the
Hb/1000 m values and the formulas provided in
Table 3A and B to adjust the low altitude anemia
threshold for altitude10 as shown in Table 4A, at
least for adult women and men. The adjustment fac-
tors previously reported by the WHO were deter-
mined from Hb values analyzed exclusively in South
American high-altitude natives and thus are not
widely applicable to other high-altitude regions of
the world. These frequently used correction factors
define wrong cutoff values resulting in false diagno-
sis. For illustration, a Tibetan or an Ethiopian native
with a normal [Hb] for his/her ethnicity and alti-
tude of residence will be considered anemic after
applying the South America-derived WHO correc-
tion factor.
It is important to note that particularly in South
American Aymaras living at moderate altitudes
application of a linear increase in [Hb] may result in
higher numbers of individuals diagnosed with ane-
mia compared with those cut-off values suggested
by WHO, where an exponential fit is applied. Most
probably, however, this is not the case for South
American Quechuas who in general show lower
[Hb] compared with Aymaras. It is unclear, whether
similar heterogeneities as seen in South America
exist in other regions of the world, too. This illus-
trates the urgent need of studying [Hb] of individ-
ual ethnicities worldwide, even within regions, in
more detail. Inappropriate cut-off levels for [Hb]
may result in unreasonably high percentages of ane-
mia causing unnecessary supplementation with iron
and other treatments.
Diagnosing erythrocytosis. At low altitude, val-
ues above a [Hb] of 18.5 g/dL for adult men and
16.5 g/dL for adult women have been defined as
cutoff values for the detection of excessive ery-
throcytosis and polycythemia,45,46 aiming mainly
at the detection of polycythemia vera, but values
have never been objectively verified.47 Changes of
cutoff values with altitude and differences among
ethnicities have not been considered so far indi-
cating that those values need to be defined. One
possible approach is the correction of these values
213
Hemoglobin levels at high altitude Gassmann et al.

Table 4. Cutoff values for the [Hb] (g/dL) to diagnose anemia (A) and erythrocytosis (B) in adult, nonpregnant
women living at different high altitude regions
Altitude (m) South American people Tibetan people Han Chinese people All others WHO altitude formula

(A) Suggested cutoff values for diagnosing anemia in women in g/dL (for men add 1 g/dL)
0 12.0 11.2 12.4 12.0 12.0
1000 13.1 11.8 13.0 12.6 12.1
1500 13.6 12.1 13.3 12.9 12.4
2000 14.1 12.4 13.6 13.2 12.7
2500 14.6 12.7 13.9 13.5 13.2
3000 15.2 13.1 14.3 13.9 13.8
3500 15.7 13.4 14.6 14.2 14.6
4000 16.2 13.7 14.9 14.5 15.4
4500 16.7 14.0 15.2 14.8 16.4
5000 17.3 14.3 15.5 15.1 17.5
(B) Suggested cutoff values for diagnosing erythrocytosis in women (for men add 2 g/dL)
0 16.5 15.7 16.9 16.5 16.5
1000 17.6 16.3 17.5 17.1 16.6
1500 18.1 16.6 17.8 17.4 16.9
2000 18.6 16.9 18.1 17.7 17.2
2500 19.1 17.2 18.4 18.0 17.7
3000 19.7 17.6 18.9 18.4 18.3
3500 20.2 17.9 19.1 18.7 19.1
4000 20.7 18.2 19.4 19.0 19.9
4500 21.2 18.5 19.7 19.3 20.9
5000 21.8 18.8 20.0 19.6 22.0

Note: Values are based on the model presented in Table 2 in comparison to the adjustments suggested by the WHO.10,46 The table
shows only values for those groups (ethnicity/country/region), where statistically significant differences (or a clear trend) existed in
the calculated [Hb] at sea level and its increase with high altitude (Table 3). According to the recommendations by the WHO, the
cutoff for anemia in adult women at sea level is defined as 12 g/dL and for polycythemia as 16.5 g/dL.46 Ethnicity/region–related dif-
ferences in low-altitude Hb values are adjusted according to Table 3A, and altitude-related changes are calculated from the respective
slope (Table 3B) and according to the formula suggested by WHO.10 Values can be applied by choosing the nearest altitude or by
extrapolation between altitude ranges. Cutoff values can be adjusted for age, pregnancy, and smoking as suggested.10

based on the results of the multiple regression
model presented here. To this end, the WHO cut-
off values for [Hb] must be corrected with the inter-
cepts (sea-level values) for the different ethnicities
as presented in Table 3A, resulting in ethnicity-
specific sea-level cutoff values. In a second step,
the ethnicity-specific increase in [Hb] with alti-
tude shown in Table 3B should be applied to calcu-
late cutoff values for specific altitudes. In Table 4B,
we exemplified such a calculation and compare the
results with adjustments for altitude as suggested by
the WHO.10 Obviously, the currently used WHO
correction results in much higher cutoff values for
altitudes above 4000 m than those after applying
our linear approach (Table 4B). It is important to
note that cutoff values at altitudes above 3000–4000
m reach Hb values higher than those suggested for
the detection of CMS.17 This indicates that at those
altitudes, more specific clinical tests are required to
distinguish, for example, polycythemia vera and
other forms of excessive erythrocytosis mostly
deriving from CMS.
Smokers. [Hb] is elevated by up to 1 g/dL in
smokers, where the degree of increase depends on
the number of cigarettes/cigars per day.16 Thus,
smoking is another source contributing to abnor-
mally high [Hb] at high altitude resulting in dif-
ficulties in reliable detection of both anemia and
polycythemia. Studies on high-altitude physiology
typically exclude smokers. Thus, we were unable
to account for this subgroup, which would have
been of importance because carboxyHb formation
decreases arterial oxygen loading and causes hypox-
emia, which stimulates erythropoiesis. This sug-
gests that effects on [Hb] of hypoxia by altitude

214 Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences.
Gassmann et al.
and smoking may be additive. In fact, it has been
shown that the elevation in [Hb] in response to
smoking is comparable at low and intermediate
altitudes.48,49
Conclusion
[Hb] is generally elevated in high-altitude residents,
but the degree of required [Hb] adjustment under
physiological conditions varies among different
regions of the world. This clearly indicates that
differences exist between ethnicities and points
to different strategies of adjustment of oxygen
transport in blood. Accordingly, these variations
render the diagnosis of anemia in high-altitude
residents a difficult task. Moreover, the standard
correction factor for [Hb] suggested by WHO
is not valid for its worldwide use. Therefore, we
established look-up tables and correction factors
to account for these differences between ethnic-
ities. Due to gaps in available literature data on
high-altitude physiology, we only can provide
information on adult women and men, whereas
data on newborns, children, and pregnant women
are incomplete. We suggest using threshold [Hb] for
the detection of anemia established for low altitude
and to apply region/ethnicity–specific regression
lines (Table 3) to extrapolate to the altitude of
residence to diagnose anemia in patients in high-
altitude clinics as shown in Table 4. Using a single
correction factor worldwide is certainly not appro-
priate. Importantly, it was outside the scope of this
analysis to establish additional correction factors,
such as for pregnancy, African origin, and smokers
at various altitudes that are frequently applied for
adjustment of [Hb] in program surveys.10 Future
studies have to be designed to fill all these gaps.
Acknowledgments
This work was commissioned by the Evidence and
Programme Guidance Unit, Department of Nutri-
tion for Health and Development of the World
Health Organization (WHO), Geneva, Switzerland.
The authors wish to thank Christiane Herth for gen-
erating the Hb-tables and for help and intense dis-
cussion. We also acknowledge the financial support
by the Zurich Center for Integrative Human Physi-
ology (ZIHP) and the Swiss National Science Foun-
dation (both to M.G.); the German Federal Min-
Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences.
Hemoglobin levels at high altitude
istry of Education and Research 82DZL00401 and
82DZL004A1 (M.U.M. and H.M).
We apologize to all those authors whose original
or review articles could not be cited due to space
limitation. Moreover, due to the keywords used for
the search, we might have missed important contri-
butions. Thus, if the reader feels that some impor-
tant publications were not considered, we kindly ask
to provide us with the suggested paper(s) so that we
can update this analysis in a future study.
Statement
Part of this manuscript was presented at the World
Health Organization (WHO) technical consultation
“Use and Interpretation of Haemoglobin Concen-
trations for Assessing Anaemia Status in Individu-
als and Populations,” held in Geneva, Switzerland
on November 29–30 and December 1, 2017. This
paper is being published individually but will be
consolidated with other manuscripts as a special
issue of Annals of the New York Academy of Sci-
ences, the coordinators of which were Drs. Maria
Nieves Garcia-Casal and Sant-Rayn Pasricha. The
special issue is the responsibility of the editorial
staff of Annals of the New York Academy of Sci-
ences, who delegated to the coordinators prelimi-
nary supervision of both technical conformity to the
publishing requirements of Annals of the New York
Academy of Sciences and general oversight of the sci-
entific merit of each article. The workshop was sup-
ported by WHO, the Centers for Disease Control
and Prevention (CDC); the United States Agency
for International Development (USAID), and the
Bill & Melinda Gates Foundation. The authors alone
are responsible for the views expressed in this
paper; they do not necessarily represent the views,
decisions, or policies of the WHO. The opinions
expressed in this publication are those of the authors
and are not attributable to the sponsors, publisher,
or editorial staff of Annals of the New York Academy
of Sciences.
Supporting information
Additional supporting information may be found in
the online version of this article.
Table S1. Summary of categories used for the
present statistical evaluation.
Table S2. Countries included in the evaluation of
Hb concentration at increasing altitudes.
215
Hemoglobin levels at high altitude
Competing interests
The authors declare no competing interests.
References
1. Mairbäurl, H. & R.E. Weber. 2012. Oxygen transport by
hemoglobin. Compr. Physiol. 2: 1463–1489.
2. Laughlin, M.H., M.J. Davis, N.H. Secher, et al. 2012.
Peripheral circulation. Compr. Physiol. 2: 321–447.
3. Siebenmann, C., P. Robach & C. Lundby. 2017. Regulation
of blood volume in lowlanders exposed to high altitude.
J. Appl. Physiol. 123. https://doi.org/10.1152/japplphysiol.
00118.2017.
4. Hurtado, A., C. Merino & E. Delgado. 1945. Influence of
anoxaemia on the hematopoietic activity. Arch. Int. Med.
75: 284–323.
5. Reynafarje, C., R. Lozano & J. Valdivieso. 1959. The poly-
cythemia of high altitudes: iron metabolism and related
aspects. Blood 14: 433–455.
6. Moore, L.G., S.S. Rounds, D. Jahnigen, et al. 1982. Infant
birth weight is related to maternal arterial oxygenation at
high altitude. J. Appl. Physiol. 52: 695–699.
7. Calbet, J.A., R. Boushel, G. Radegran, et al. 2003. Why is
VO2 max after altitude acclimatization still reduced despite
normalization of arterial O2 content? Am. J. Physiol. 284:
R304–R316.
8. Gassmann, M. & M.U. Muckenthaler. 2015. Adaptation of
iron requirement to hypoxic conditions at high altitude.
J. Appl. Physiol. 119: 1432–1440.
9. Muckenthaler, M.U., S. Rivella, M.W. Hentze, et al. 2017. A
red carpet for iron metabolism. Cell 168: 344–361.
10. Nestel, P. 2002. Adjusting hemoglobin values for program
surveys. International Nutritional Anemia Consultative
Group (INACG).
11. Simonson, T.S., Y. Yang, C.D. Huff, et al. 2010. Genetic evi-
dence for high-altitude adaptation in Tibet. Science 329:
72–75.
12. Beall, C.M., G.M. Brittenham, F. Macuaga, et al. 1990. Vari-
ation in hemoglobin concentration among samples of high-
altitude natives in the Andes and the Himalayas. Am. J.
Hum. Biol. 2: 639–651.
13. Beall, C.M., M.J. Decker, G.M. Brittenham, et al. 2002. An
Ethiopian pattern of human adaptation to high-altitude
hypoxia. Proc. Natl. Acad. Sci. USA 99 17215–17218.
14. Tashi, T., N.S. Reading, T. Wuren, et al. 2017. Gain-of-
function EGLN1 prolyl hydroxylase (PHD2 D4E: C127S)
in combination with EPAS1(HIF-2α) polymorphism low-
ers hemoglobin concentration in Tibetan highlanders.
J. Mol. Med. 95: 665–670.
15. Fulwood, R., C.L. Johnson, J.D. Bryner, et al. 1982. Hema-
tological and nutritional biochemistry data for persons 6
months–74 years of age: United States, 1976–80. DHHS
Publication No. (PHS) 83–1682. 1–183.
16. Centers for Disease Control (CDC). 1989. Criteria for ane-
mia in children and childbearing-aged women. MMWR
Morb. Mortal. Wkly. Rep. 38: 400–404.
17. Leon-Velarde, F., M. Maggiorini, J.T. Reeves, et al. 2005.
Consensus statement on chronic and subacute high alti-
tude diseases. High Alt. Med. Biol. 6: 147–157.
216 Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences.
Gassmann et al.
18. Beall, C.M. 2006. Andean, Tibetan, and Ethiopian patterns
of adaptation to high-altitude hypoxia. Integr. Comp. Biol.
46: 18–24.
19. Hozo, S.P., B. Djulbegovic & I. Hozo. 2005. Estimating the
mean and variance from the median, range, and the size of
a sample. BMC Med. Res. Methodol. 5: 13.
20. Wan, X., W. Wang, J. Liu, et al. 2014. Estimating the sample
mean and standard deviation from the sample size, median,
range and/or interquartile range. BMC Med. Res. Methodol.
14: 135.
21. Spiegelhalder, D.J., K.R. Abrams & J.P. Myles. 2004.
Bayesian Approaches to Clinical Trials and Health Care
Evaluation. Wiley & Sons.
22. Roever, C. 2017. bayesmeta: bayesian random-effects
meta-analysis. R package version 1.5. https://CRAN.R-
project.org/package=bayesmeta. Accessed June 7, 2019.
23. Schwarzer, G. 2007. Meta: an R-package for meta-analysis.
R News. 7, 40–45.
24. Viault, F. 1891. Sur la quantite d’oxygene contenue dans la
sang des animoux des hauts plateaux de l’Amerique du Sud.
CRH Acad. Sci. Paris 112: 295.
25. Arnaud, J., J.C. Quilici & G. Riviere. 1981. High-altitude
haematology: Quechua–Aymara comparisons. Ann. Hum.
Biol. 8: 573–578.
26. Groves, B.M., T. Droma, J.R. Sutton, et al. 1993. Minimal
hypoxic pulmonary hypertension in normal Tibetans at
3,658 m. J. Appl. Physiol. 74: 312–318.
27. Winslow, R.M., K.W. Chapman, C.C. Gibson, et al. 1989.
Different hematologic responses to hypoxia in Sherpas and
Quechua Indians. J. Appl. Physiol. 66: 1561–1569.
28. Petousi, N., Q.P. Croft, G.L. Cavalleri, et al. 2014. Tibetans
living at sea level have a hyporesponsive hypoxia-inducible
factor system and blunted physiological responses to
hypoxia. J. Appl. Physiol. 116: 893–904.
29. Lorenzo, F.R., C. Huff, M. Myllymaki, et al. 2014. A
genetic mechanism for Tibetan high-altitude adaptation.
Nat. Genet. 46: 951–956.
30. Simonson, T.S., D.A. McClain, L.B. Jorde, et al. 2012.
Genetic determinants of Tibetan high-altitude adaptation.
Hum. Genet. 131: 527–533.
31. Moore, L.G. 2000. Comparative human ventilatory adapta-
tion to high altitude. Resp. Physiol. 121: 257–276.
32. Winslow, R.M. & C. Monge. 1987. Hypoxia, Polycythemia,
and Chronic Mountain Sickness. Baltimore, MD: Johns
Hopkins University Press.
33. Cosio, G. & A. Yataco. 1968. Valores de hemoglobina en
relacion con la altura sobre el nivel del mar. Rev. Sal. Occup.
13: 5–17.
34. Dirren, H., M.H. Logman, D.V. Barclay, et al. 1994. Alti-
tude correction for hemoglobin. Eur. J. Clin. Nutr. 48: 625–
632.
35. Data, P.G., M. Cacchio, C. Monge, et al. 1981. [Evalua-
tion of various hematologic parameters in Andean miners
(Morococha-Peru 4560 m)]. Boll. Soc. Ital. Biol. Sper. 57:
1411–1416.
36. Humpeler, E., S. Vogel, W. Schobersberger, et al. 1989. Red
cell oxygen transport in man in relation to gender and age.
Mech. Aging Dev. 47: 229–239.
37. Bassuni, W., A.A. Asindi, F.S. Mustafa, et al. 1996.
Hemoglobin and hematocrit values of Saudi newborns in
Gassmann et al.
the high altitude of Abha, Saudi Arabia. Ann. Saudi Med.
16: 527–529.
38. Niermeyer, S., P. Yang, Shanmina, et al. 1995. Arterial oxy-
gen saturation in Tibetan and Han infants born in Lhasa,
Tibet. N. Engl. J. Med. 333: 1248–1252.
39. Gassmann, N.N., H.A. van Elteren, T.G. Goos, et al. 2016.
Pregnancy at high altitude in the Andes leads to increased
total vessel density in healthy newborns. J. Appl. Physiol.
121: 709–715.
40. Garruto, R.M., C.T. Chin, C.A. Weitz, et al. 2003. Hemato-
logical differences during growth among Tibetans and Han
Chinese born and raised at high altitude in Qinghai, China.
Am. J. Phys. Anthropol. 122: 171–183.
41. Wu, T., X. Wang, C. Wei, et al. 2005. Hemoglobin levels in
Qinghai-Tibet: different effects of gender for Tibetans vs.
Han. J. Appl. Physiol. 98: 598–604.
42. Garruto, R.M. & J.S. Dutt. 1983. Lack of prominent com-
pensatory polycythemia in traditional native Andeans liv-
ing at 4,200 meters. Am. J. Phys. Anthropol. 61: 355–
366.
43. Vargas, M., E. Vargas, C.G. Julian, et al. 2007. Determi-
nants of blood oxygenation during pregnancy in Andean
and European residents of high altitude. Am. J. Physiol. 293:
R1303–R1312.
44. Zamudio, S., S.K. Palmer, T.E. Dahms, et al. 1993. Blood
volume expansion, preeclampsia, and infant birth weight
at high altitude. J. Appl. Physiol. 75: 1566–1573.
45. Keohane, C., M.F. McMullin & C. Harrison. 2013. The
diagnosis and management of erythrocytosis. BMJ 347:
f6667.
46. Tefferi, A., J. Thiele, A. Orazi, et al. 2007. Proposals and
rationale for revision of the World Health Organization
diagnostic criteria for polycythemia vera, essential throm-
bocythemia, and primary myelofibrosis: recommendations
from an ad hoc international expert panel. Blood 110:
1092–1097.
47. Silver, R.T., W. Chow, A. Orazi, et al. 2013. Evaluation
of WHO criteria for diagnosis of polycythemia vera: a
prospective analysis. Blood 122: 1881–1886.
48. Brewer, G.J., C.F. Sing, J.W. Eaton, et al. 1974. Effects on
hemoglobin oxygen affinity of smoking in residents of
intermediate altitude. J. Lab. Clin. Med. 84: 191–205.
49. Wu, T.Y., S.Q. Ding, J.L. Liu, et al. 2012. Smoking, acute
mountain sickness and altitude acclimatisation: a cohort
study. Thorax 67: 914–919.
50. Ozyurek, E., S. Cetintas, T. Ceylan, et al. 2006. Complete
blood count parameters for healthy, small-for-gestational-
age, full-term newborns. Clin. Lab. Haematol. 28: 97–104.
51. Bianba, S., Berntsen, L.B. Andersen, et al. 2014. Exer-
cise capacity and selected physiological factors by ances-
try and residential altitude: cross-sectional studies of 9–10-
year-old children in Tibet. High Alt. Med. Biol. 15: 162–
169.
52. Dang, S., H. Yan, S. Yamamoto, et al. 2004. Poor nutritional
status of younger Tibetan children living at high altitudes.
Eur. J. Clin. Nutr. 58: 938–946.
53. Hirschler, V., G. Maccallini, C. Aranda, et al. 2012. Dyslipi-
demia without obesity in indigenous Argentinean children
living at high altitude. J. Pediatr. 161: 646–651.e1.
Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences.
Hemoglobin levels at high altitude
54. Hirschler, V., G. Maccallini, C. Molinari, et al. 2013. Low
vitamin D concentrations among indigenous Argentinean
children living at high altitudes. Pediatr. Diabetes 14: 203–
210.
55. Leon-Velarde, F., A. Gamboa, J.A. Chuquiza, et al. 2000.
Hematological parameters in high altitude residents living
at 4,355, 4,660, and 5,500 meters above sea level. High Alt.
Med. Biol. 1: 97–104.
56. Crapo, R.O., R.L. Jensen, M. Hegewald, et al. 1999. Arterial
blood gas reference values for sea level and an altitude of
1,400 meters. Am. J. Respir. Crit. Care Med. 160: 1525–1531.
57. Fitzgerald, M.P. 1913. The changes in the breathing and the
blood at various high altitudes. Philos. Trans. R. Soc. Lond.
13: 103.
58. Brothers, M.D., R.L. Wilber & W.C. Byrnes. 2007. Physical
fitness and hematological changes during acclimatization
to moderate altitude: a retrospective study. High Alt. Med.
Biol. 8: 213–224.
59. Brothers, M.D., B.K. Doan, M.F. Zupan, et al. 2010. Hema-
tological and physiological adaptations following 46 weeks
of moderate altitude residence. High Alt. Med. Biol. 11:
199–208.
60. Nuss, R., J.P. Loehr, E. Daberkow, et al. 1993. Cardiopul-
monary function in men with sickle cell trait who reside at
moderately high altitude. J. Lab. Clin. Med. 122: 382–387.
61. Ruiz-Arguelles, G.J., L. Sanchez-Medal, A. Loria, et al.
1980. Red cell indices in normal adults residing at alti-
tude from sea level to 2670 meters. Am. J. Hematol. 8: 265–
271.
62. Gonzales, G.F., R. Lozano-Hernandez, M. Gasco, et al.
2012. Resistance of sperm motility to serum testosterone in
men with excessive erythrocytosis at high altitude. Horm.
Metab. Res. 44: 987–992.
63. Gonzales, G.F., M. Gasco, V. Tapia, et al. 2009. High serum
testosterone levels are associated with excessive erythrocy-
tosis of chronic mountain sickness in men. Am. J. Physiol.
296: E1319–E1325.
64. Gonzales, G.F., V. Tapia, M. Gasco, et al. 2012. Aromatase
activity after a short-course of letrozole administration in
adult men at sea level and at high altitude (with or without
excessive erythrocytosis). Horm. Metab. Res. 44: 140–145.
65. Robles Gil, J. & D. Gonzalez Teran. 1948. Determination
of the number of erythrocytes, volume of packed red cells,
hemoglobin and other hematologic standards in Mexico
City, altitude, 7,457 feet; study made on 200 healthy per-
sons. Blood 3: 660–681.
66. Böning, D., J. Rojas, M. Serrato, et al. 2001. Hemoglobin
mass and peak oxygen uptake in untrained and trained res-
idents of moderate altitude. Int. J. Sports Med. 22: 572–
578.
67. Cristancho, E., A. Riveros, A. Sanchez, et al. 2016. Diur-
nal changes of arterial oxygen saturation and erythropoi-
etin concentration in male and female highlanders. Physiol.
Rep. 4. https://doi.org/10.14814/phy2.12901.
68. Crowley, C., G. Montenegro-Bethancourt, N.W. Solomons,
et al. 2012. Validity and correspondence of non-invasively
determined hemoglobin concentrations by two trans-
cutaneous digital measuring devices. Asia Pac. J. Clin. Nutr.
21: 191–200.
217
Hemoglobin levels at high altitude
69. Barclay, D.V., L. Heredia, J. Gil-Ramos, et al. 1996. Nutri-
tional status of institutionalised elderly in Ecuador. Arch.
Latinoam. Nutr. 46: 122–127.
70. Julian, C.G., E. Vargas, M. Gonzales, et al. 2013. Sleep-
disordered breathing and oxidative stress in preclinical
chronic mountain sickness (excessive erythrocytosis).
Respir. Physiol. Neurobiol. 186: 188–196.
71. Tufts, D.A., J.D. Haas, J.L. Beard, et al. 1985. Distribution
of hemoglobin and functional consequences of anemia in
adult males at high altitude. Am. J. Clin. Nutr. 42: 1–11.
72. Pratali, L., Y. Allemann, S.F. Rimoldi, et al. 2013. RV con-
tractility and exercise-induced pulmonary hypertension in
chronic mountain sickness: a stress echocardiographic and
tissue Doppler imaging study. JACC Cardiovasc. Imaging 6:
1287–1297.
73. Beard, J.L., J.D. Haas, D. Tufts, et al. 1988. Iron deficiency
anemia and steady-state work performance at high altitude.
J. Appl. Physiol. 64: 1878–1884.
74. Beall, C.M., G.M. Brittenham, K.P. Strohl, et al. 1998.
Hemoglobin concentration of high-altitude Tibetans and
Bolivian Aymara. Am. J. Phys. Anthropol. 106: 385–
400.
75. Vasquez, R. & M. Villena. 2001. Normal hematological val-
ues for healthy persons living at 4000 meters in Bolivia.
High Alt. Med. Biol. 2: 361–367.
76. Gonzales, G.F., J. Rubio & M. Gasco. 2013. Chronic moun-
tain sickness score was related with health status score but
not with hemoglobin levels at high altitudes. Respir. Physiol.
Neurobiol. 188: 152–160.
77. Leon-Velarde, F., A. Arregui, M. Vargas, et al. 1994.
Chronic mountain sickness and chronic lower respiratory
tract disorders. Chest 106: 151–155.
78. Mejia, O.M., J.T. Prchal, F. Leon-Velarde, et al. 2005.
Genetic association analysis of chronic mountain sickness
in an Andean high-altitude population. Haematologica 90:
13–19.
79. Winslow, R.M., C.C. Monge, N.J. Statham, et al. 1981. Vari-
ability of oxygen affinity of blood: human subjects native to
high altitude. J. Appl. Physiol. 51: 1411–1416.
80. Tarazona-Santos, E., M. Lavine, S. Pastor, et al. 2000.
Hematological and pulmonary responses to high altitude
in Quechuas: a multivariate approach. Am. J. Phys. Anthro-
pol. 111: 165–176.
81. Morris, C.D. & D. Dickson. 1989. Haematological refer-
ence values in adult blacks at sea level. Afr. Med. J. 75:
35–36.
82. Levy, S.B. 1969. Hemoglobin differences among Kenyan
tribes. A survey of eight tribes in seventeen areas of the
country. Am. J. Trop. Med. Hyg. 18: 138–146.
83. Buchanan, A.M., F.J. Muro, J. Gratz, et al. 2010. Establish-
ment of haematological and immunological reference val-
ues for healthy Tanzanian children in Kilimanjaro Region.
Trop. Med. Int. Health 15: 1011–1021.
84. Saathoff, E., P. Schneider, V. Kleinfeldt, et al. 2008. Labora-
tory reference values for healthy adults from southern Tan-
zania. Trop. Med. Int. Health 13: 612–625.
85. Tikly, M., D. Blumsohn, H.D. Solomons, et al. 1987. Nor-
mal haematological reference values in the adult black pop-
ulation of the Witwatersrand. S. Afr. Med. J. 72: 135–136.
218 Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences.
Gassmann et al.
86. Gahutu, J.B., J. Wane, J. d’Arc Uwambazimana, et al. 2005.
A Rwandan altitude blood gas, acid-base and hemoglobin
study. Clin. Chim. Acta 357: 86–87.
87. Prommer, N., S. Thoma, L. Quecke, et al. 2010. Total
hemoglobin mass and blood volume of elite Kenyan run-
ners. Med. Sci. Sports Exerc. 42: 791–797.
88. Scheinfeldt, L.B., S. Soi, S. Thompson, et al. 2012. Genetic
adaptation to high altitude in the Ethiopian highlands.
Genome Biol. 13: R1.
89. Lundgrin, E.L., A.J. Janocha, C.D. Koch, et al. 2013.
Plasma hepcidin of Ethiopian highlanders with steady-
state hypoxia. Blood 122: 1989–1991.
90. Cheong, H.I., A.J. Janocha, L.T. Monocello, et al. 2017.
Alternative hematological and vascular adaptive responses
to high-altitude hypoxia in East African highlanders. Am.
J. Physiol. 312: L172–L177.
91. Alkorta-Aranburu, G., C.M. Beall, D.B. Witonsky, et al.
2012. The genetic architecture of adaptations to high alti-
tude in Ethiopia. PLoS Genet. 8: e1003110.
92. Al-Sweedan, S.A. & M. Alhaj. 2012. The effect of low alti-
tude on blood count parameters. Hematol. Oncol. Stem Cell
Ther. 5: 158–161.
93. Fiori, G., F. Facchini, O. Ismagulov, et al. 2000. Lung
volume, chest size, and hematological variation in low-,
medium-, and high-altitude central Asian populations.
Am. J. Phys. Anthropol. 113: 47–59.
94. Baskurt, O.K., E. Levi, S. Caglayan, et al. 1990. Hematologi-
cal and hemorheological effects of air pollution. Arch. Env-
iron. Health 45: 224–228.
95. Shahshahani, H.J., N. Meraat & F. Mansouri. 2013. Evalu-
ation of the validity of a rapid method for measuring high
and low haemoglobin levels in whole blood donors. Blood
Transfus. 11: 385–390.
96. Kaya, H., I. Kiki, E. Akarsu, et al. 2000. Hematological val-
ues of healthy adult population living at moderate altitude
(1869 m, Erzurum, Turkey). Turk. J. Haematol. 17: 123–
128.
97. Guan, W., X. Li, Y.Z. Yang, et al. 2013. [Serum levels and
significance of HIF-1α and HIF-2α in healthy Tibetan and
Han residents at different altitudes]. Zhonghua Yi Xue Za
Zhi 93: 3057–3059.
98. Yan, Y., C. Wang, W. Zhou, et al. 2016. Elevation of circu-
lating miR-210-3p in high-altitude hypoxic environment.
Front. Physiol. 7: 84.
99. Yan, Y., Y. Shi, C. Wang, et al. 2015. Influence of a
high-altitude hypoxic environment on human plasma
microRNA profiles. Sci. Rep. 5: 15156.
100. Wu, X., M. Zhao, B. Pan, et al. 2015. Complete blood count
reference intervals for healthy Han Chinese adults. PLoS
One 10: e0119669.
101. Zhong, R., H. Liu, H. Wang, et al. 2015. Adaption to high
altitude: an evaluation of the storage quality of suspended
red blood cells prepared from the whole blood of Tibetan
plateau migrants. PLoS One 10: e0144201.
102. Okumiya, K., R. Sakamoto, Y. Kimura, et al. 2009. Com-
prehensive geriatric assessment of elderly highlanders in
Qinghai, China II: the association of polycythemia with
lifestyle-related diseases among the three ethnicities. Geri-
atr. Gerontol. Int. 9: 342–351.
Gassmann et al.
103. Huang, S.Y., S. Sun, T. Droma, et al. 1992. Internal carotid
arterial flow velocity during exercise in Tibetan and Han
residents of Lhasa (3,658 m). J. Appl. Physiol. 73: 2638–
2642.
104. Sun, S., C. Oliver-Pickett, Y. Ping, et al. 1996. Breathing
and brain blood flow during sleep in patients with chronic
mountain sickness. J. Appl. Physiol. 81: 611–618.
105. Buroker, N.E., X.H. Ning, Z.N. Zhou, et al. 2012.
AKT3, ANGPTL4, eNOS3, and VEGFA associations with
high altitude sickness in Han and Tibetan Chinese at
the Qinghai-Tibetan Plateau. Int. J. Hematol. 96: 200–
213.
106. Simonson, T.S., G. Wei, H.E. Wagner, et al. 2014.
Increased blood–oxygen binding affinity in Tibetan and
Han Chinese residents at 4200 m. Exp. Physiol. 99: 1624–
1635.
107. Jiang, C., J. Chen, F. Liu, et al. 2014. Chronic mountain sick-
ness in Chinese Han males who migrated to the Qinghai-
Tibetan plateau: application and evaluation of diagnostic
criteria for chronic mountain sickness. BMC Public Health
14: 701.
108. Chen, Y., C. Jiang, Y. Luo, et al. 2014. An EPAS1 haplotype
is associated with high altitude polycythemia in male Han
Chinese at the Qinghai-Tibetan plateau. Wilderness Envi-
ron. Med. 25: 392–400.
109. Moore, L.G., S. Zamudio, J. Zhuang, et al. 2002. Analysis of
the myoglobin gene in Tibetans living at high altitude. High
Alt. Med. Biol. 3: 39–47.
110. Beall, C.M. & A.B. Reichsman. 1984. Hemoglobin levels in
a Himalayan high altitude population. Am. J. Phys. Anthro-
pol. 63: 301–306.
111. Curran, L.S., J. Zhuang, T. Droma, et al. 1995. Hypoxic
ventilatory responses in Tibetan residents of 4400
m compared with 3658 m. Respir. Physiol. 100: 223–
230.
112. Xu, J., Y.Z. Yang, F. Tang, et al. 2015. CYP17A1 and CYP2E1
variants associated with high altitude polycythemia in
Tibetans at the Qinghai-Tibetan Plateau. Gene 566: 257–
263.
113. Erzurum, S.C., S. Ghosh, A.J. Janocha, et al. 2007. Higher
blood flow and circulating NO products offset high-
altitude hypoxia among Tibetans. Proc. Natl. Acad. Sci. USA
104: 17593–17598.
114. Hoit, B.D., N.D. Dalton, S.C. Erzurum, et al. 2005. Nitric
oxide and cardiopulmonary hemodynamics in Tibetan
highlanders. J. Appl. Physiol. 99: 1796–1801.
115. Adams, W.H. & L.J. Strang. 1975. Hemoglobin levels on
persons of Tibetan ancestry living at high altitude. Proc.
Soc. Exp. Biol. Med. 149: 1036–1039.
116. Beall, C.M. & M.C. Goldstein. 1987. Hemoglobin concen-
tration of pastoral nomads permanently resident at 4,850–
5,450 meters in Tibet. Am. J. Phys. Anthropol. 73: 433–
438.
117. Morpurgo, G., P. Arese, A. Bosia, et al. 1976. Sherpas living
permanently at high altitude: a new pattern of adaptation.
Proc. Natl. Acad. Sci. USA 73: 747–751.
118. Bhandari, S., X. Zhang, C. Cui, et al. 2017. Sherpas share
genetic variations with Tibetans for high-altitude adapta-
tion. Mol. Genet. Genomic Med. 5: 76–84.
Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences.
Hemoglobin levels at high altitude
119. Marconi, C., M. Marzorati, B. Grassi, et al. 2004. Sec-
ond generation Tibetan lowlanders acclimatize to high alti-
tude more quickly than Caucasians. J. Physiol. 556: 661–
671.
120. Samaja, M. & R.M. Winslow. 1979. The separate effects
of H+ and 2,3-DPG on the oxygen equilibrium curve of
human blood. Br. J. Haematol. 41: 373–381.
121. Jeong, C., G. Alkorta-Aranburu, B. Basnyat, et al. 2014.
Admixture facilitates genetic adaptations to high altitude
in Tibet. Nat. Commun. 5: 3281.
122. Robertson, R.J., R. Gilcher, K.F. Metz, et al. 1988. Effect
of simulated altitude erythrocythemia in women on
hemoglobin flow rate during exercise. J. Appl. Physiol. 64:
1644–1649.
123. Cristancho, E., O. Reyes, M. Serrato, et al. 2007. Arte-
rial oxygen saturation and hemoglobin mass in post-
menopausal untrained and trained altitude residents. High
Alt. Med. Biol. 8: 296–306.
124. Moore, L.G., P. Brodeur, O. Chumbe, et al. 1986. Mater-
nal hypoxic ventilatory response, ventilation, and infant
birth weight at 4,300 m. J. Appl. Physiol. 60: 1401–
1406.
125. Bigham, A.W., M.J. Wilson, C.G. Julian, et al. 2013. Andean
and Tibetan patterns of adaptation to high altitude. Am. J.
Hum. Biol. 25: 190–197.
126. Berger, J., V.M. Aguayo, J.L. San Miguel, et al. 1997. Defini-
tion and prevalence of anemia in Bolivian women of child-
bearing age living at high altitudes: the effect of iron-folate
supplementation. Nutr. Rev. 55: 247–256.
127. Julian, C.G., J.L. Hageman, M.J. Wilson, et al. 2011. Low-
land origin women raised at high altitude are not protected
against lower uteroplacental O2 delivery during pregnancy
or reduced birth weight. Am. J. Hum. Biol. 23: 509–
516.
128. Postigo, L., G. Heredia, N.P. Illsley, et al. 2009. Where the
O2 goes to: preservation of human fetal oxygen delivery
and consumption at high altitude. J. Physiol. 587: 693–
708.
129. Leon-Velarde, F., M. Rivera-Chira, R. Tapia, et al. 2001.
Relationship of ovarian hormones to hypoxemia in
women residents of 4,300 m. Am. J. Physiol. 280: R488–
R493.
130. Harvey-Leeson, S., C.D. Karakochuk, M. Hawes, et al.
2016. Anemia and micronutrient status of women of child-
bearing age and children 6–59 months in the Democratic
Republic of the Congo. Nutrients 8: 98.
131. Cross, J.P. & A.D. Heyns. 1983. Haematological refer-
ence values for the Basotho. S. Afr. Med. J. 63: 480–
483.
132. Ross, S.M. 1972. Haemoglobin and haematocrit values
in pregnant women on a high iron intake and living
at a high altitude. Br. J. Obstet. Gynaecol. 79: 1103–
1107.
133. Beall, C.M., A. Gebremedhin, G.M. Brittenham, et al. 1997.
Blood pressure variation among Ethiopians on the Simien
Plateau. Ann. Hum. Biol. 24: 333–342.
134. Moore, L.G., S. Zamudio, J.G. Zhuang, et al. 2001. Oxygen
transport in Tibetan women during pregnancy at 3,658 m.
Am. J. Phys. Anthropol. 114: 42–53.
219
Hemoglobin levels at high altitude
135. Moore, L.G. 1990. Maternal O2 transport and fetal growth
in Colorado, Peru, and Tibet high-altitude residents. Am. J.
Hum. Biol. 2: 627–637.
136. Gonzales, G.F., K. Steenland & V. Tapia. 2009. Maternal
hemoglobin level and fetal outcome at low and high alti-
tudes. Am. J. Physiol. 297: R1477–R1485.
137. Laflamme, E.M. 2011. Maternal hemoglobin concentra-
tion and pregnancy outcome: a study of the effects
of elevation in El Alto, Bolivia. McGill J. Med. 13:
47.
138. Hinderaker, S.G., B.E. Olsen, P. Bergsjo, et al. 2001. Ane-
mia in pregnancy in the highlands of Tanzania. Acta Obstet.
Gynecol. Scand. 80: 18–26.
139. Umar, Z., M. Rasool, M. Asif, et al. 2015. Evaluation of
hemoglobin concentration in pregnancy and correlation
220 Ann. N.Y. Acad. Sci. 1450 (2019) 204–220 © 2019 New York Academy of Sciences.
Gassmann et al.
with different altitude: a study from Balochistan plateau of
Pakistan. Open Biochem. J. 9: 7–14.
140. Khalid, M.E., M.E. Ali & K.Z. Ali. 1997. Full-term birth
weight and placental morphology at high and low altitude.
Int. J. Gynaecol. Obstet. 57: 259–265.
141. Karimi, M., R. Kadivar & H. Yarmohammadi. 2002. Assess-
ment of the prevalence of iron deficiency anemia, by serum
ferritin, in pregnant women of Southern Iran. Med. Sci.
Monit. 8: CR488–C492.
142. Xing, Y., H. Yan, S. Dang, et al. 2009. Hemoglobin levels
and anemia evaluation during pregnancy in the highlands
of Tibet: a hospital-based study. BMC Public Health 9: 336.
143. Kang, Y., F. Li, S. Dang, et al. 2014. [Study on the
hemoglobin levels among the Tibetan pregnant women in
rural Lhasa]. Zhonghua Yu Fang Yi Xue Za Zhi 48: 396–400.